Diaza heterocyclic amide compounds and their uses

ABSTRACT

Diaza heterocyclic amide derivatives according to Formula (I) have therapeutic utility, particularly in the treatment of diabetes, obesity and related conditions and disorders: 
     
       
         
         
             
             
         
       
     
     where R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, Q, X, and Y are set forth in the description.

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/784,753, which was filed on Mar. 23, 2006.

BACKGROUND OF THE INVENTION

This invention is generally directed to novel compounds, compositions,and the use of either in methods for modulating hydroxysteroiddehydrogenases, such as 11β-HSD1, and for treating or preventingdiseases associated with the modulation of hydroxysteroiddehydrogenases, such as diabetes and obesity. The methods comprise theadministration, to a patient in need thereof, of a therapeuticallyeffective amount of a diaza heterocyclic amide derivative. Novel diazaheterocyclic amide derivatives or pharmaceutically acceptable salts,solvates, stereoisomers, or prodrugs thereof are presented herein.

Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy andactivation of steroid hormone receptors by converting steroid hormonesinto their inactive metabolites. For a recent review, see Nobel et al.,Eur. J. Biochem. 2001, 268:4113-4125.

There exist numerous classes of HSDs. The 11-beta-hydroxysteroiddehydrogenases (11β-HSDs) catalyze the interconversion of activeglucocorticoids (such as cortisol and corticosterone), and their inertforms (such as cortisone and 11-dehydrocorticosterone). The isoform11′-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed inliver, adipose tissue, brain, lung and other glucocorticoid tissue andis a potential target for therapy directed at numerous disorders thatcan be ameliorated by reduction of glucocorticoid action, such asdiabetes, obesity and age-related cognitive dysfunction. Seckl, et al.,Endocrinology, 2001, 142:1371-1376.

It is well known that glucocorticoids play a central role in thedevelopment of diabetes and that glucocorticoids enable the effect ofglucagon on the liver. Long et al., J. Exp. Med. 1936, 63: 465-490; andHoussay, Endocrinology 1942, 30: 884-892. In addition, it has been wellsubstantiated that 11β-HSD1 plays an important role in the regulation oflocal glucocorticoid effect and of glucose production in the liver.Jamieson et al., J. Endocrinol. 2000, 165:685-692.

Furthermore, the hypothesized mechanism of action of HSDs in thetreatment of diabetes has been supported by various experimentsconducted in mice and rats. These studies showed that the mRNA levelsand activities of two key enzymes in hepatic glucose production,phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase(G6Pase) were reduced upon administration of HSD inhibitors. Inaddition, blood glucose levels and hepatic glucose production were shownto be reduced in 11β-HSD1 knockout mice. Additional data gathered usingthis murine knockout model also confirm that inhibition of 11β-HSD1 willnot cause hypoglycemia, since the basal levels of PEPCK and G6Pase areregulated independently of glucocorticoids. Kotelevtsev et al., Proc.Natl. Acad. Sci. USA 1997, 94: 14924-14929.

HSDs also play a role in obesity. Obesity is an important factor inSyndrome X as well as type II (non-insulin dependent) diabetes, andomental fat appears to be of central importance in the development ofboth of these disease, as abdominal obesity has been linked with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other factorsof Syndrome X (e.g., raised blood pressure, decreased levels of HDL andincreased levels of VLDL). Montague et al., Diabetes 2000, 49:883-888,2000. It has also been reported that inhibition of the 11β-HSDs inpre-adipocytes (stromal cells) resulted in a decreased rate ofdifferentiation into adipocytes. This is predicted to result indiminished expansion (possibly reduction) of the omental fat depot,which may lead to reduced central obesity. Bujalska et al., Lancet 1997,349:1210-1213.

Inhibition of 11β-HSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1), which is anindependent cardiovascular risk factor, as reported in Halleux et al.,J. Clin. Endocrinol. Metab. 1999, 84:4097-4105. In addition, acorrelation has been shown to exist between glucocorticoid activity andcertain cardiovascular risk factors. This suggests that a reduction ofthe glucocorticoid effects would be beneficial in the treatment orprevention of certain cardiovascular diseases. Walker et al.,Hypertension 1998, 31:891-895; and Fraser et al., Hypertension 1999,33:1364-1368.

HSDs have also been implicated in the process of appetite control andtherefore are believed to play an additional role in weight-relateddisorders. It is known that adrenalectomy attenuates the effect offasting to increase both food intake and hypothalamic neuropeptide Yexpression. This suggests that glucocorticoids play a role in promotingfood intake and that inhibition of 11β-HSD1 in the brain may increasesatiety, thus resulting in a decreased food intake. Woods et al.,Science 1998, 280:1378-1383.

Another possible therapeutic effect associated with modulation of HSDsis that which is related to various pancreatic aliments. It is reportedthat inhibition of 11β-HSD1 in murine pancreatic β-cells results inincreased insulin secretion. Davani et al., J. Biol. Chem. 2000,275:34841-34844. This follows from the discovery that glucocorticoidswere previously found to be responsible for reduced pancreatic insulinrelease in vivo, Billaudel et al., Horm. Metab. Res. 1979, 11:555-560.Thus, it is suggested that inhibition of 11β-HSD1 would yield otherbeneficial effects in the treatment of diabetes in addition to thepredicted effects on the liver and fat reduction.

11β-HSD1 also regulates glucocorticoid activity in the brain and thuscontributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16:65-70;and Seckl et al., Neuroendocrinol. 2000, 18:49-99. Stress and/orglucocorticoids are known to influence cognitive function (de Quervainet al., Nature 1998, 394:787-790), and unpublished results indicatesignificant memory improvement in rats treated with a non-specific11β-HSD inhibitor. These reports, in addition to the known effects ofglucocorticoids in the brain, suggest that inhibiting HSDs in the brainmay have a positive therapeutic effect against anxiety and relatedconditions. Tronche et al., Nature Genetics 1999, 23:99-103. 11β-HSD1reactivates 11-DHC to corticosterone in hippocampal cells and canpotentiate kinase neurotoxicity, resulting in age-related learningimpairments. Therefore, selective inhibitors of 11β-HSD1 are believed toprotect against hippocampal function decline with age. Yau et al., ProcNatl. Acad. Sci. USA 2001, 98:4716-4721. Thus, it has been hypothesizedthat inhibition of 11β-HSD1 in the human brain would protect againstdeleterious glucocorticoid-mediated effects on neuronal function, suchas cognitive impairment, depression, and increased appetite.

HSDs are believed to play a role in immunomodulation based on thegeneral perception that glucocorticoids suppress the immune system.There is known to be a dynamic interaction between the immune system andthe HPA (hypothalamopituitary-adrenal) axis (Rook, Baillier's Clin.Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help balancebetween cell-mediated responses and humoral responses. Increasedglucocorticoid activity, which can be induced by stress, is associatedwith a humoral response and as such, the inhibition of 11β-HSD1 mayresult in shifting the response towards a cell-based reaction. Incertain disease states, such as tuberculosis, leprosy, and psoriasis,the immune reaction is typically biased towards a humoral response whena cell-based response might be more appropriate. Inhibition of 11β-HSD1is being studied for use to direct a cell-based response in theseinstances. Mason, Immunology Today 1991, 12:57-60. It follows then, thatan alternative utility of 11β-HSD1 inhibition would be to bolster atemporal immune response in association with immunization to ensure thata cell based response would be obtained.

Recent reports suggest that the levels of glucocorticoid targetreceptors and of HSDs are connected with the risks of developingglaucoma. Stokes et al., Invest. Opthalmol. 2000, 41:1629-1638. Further,a connection between inhibition of 11β-HSD1 and a lowering of theintraocular pressure was reported. Walker et al., poster P3-698 at theEndocrine society meeting Jun. 12-15, 1999, San Diego. It was shown thatadministration of the nonspecific 11β-HSD1 inhibitor, carbenoxolone,resulted in the reduction of the intraocular pressure by 20% in normalpatients. In the eye, 11β-HSD1 is expressed exclusively in the basalcells of the corneal epithelium, the non-pigmented epithelialium of thecornea (the site of aqueous production), ciliary muscle, and thesphincter and dilator muscles of the iris. In contrast, the distantisoenzyme 11β-hydroxysteroid dehydrogenase type 2 (“11β-HSD2”) is highlyexpressed in the non-pigmented ciliary epithelium and cornealendothelium. No HSDs have been found at the trabecular meshwork, whichis the site of drainage. Therefore, 11β-HSD1 is suggested to have a rolein aqueous production.

Glucocorticoids also play an essential role in skeletal development andfunction but are detrimental to such development and function whenpresent in excess. Glucocorticoid-induced bone loss is partially derivedfrom suppression of osteoblast proliferation and collagen synthesis, asreported in Kim et al., J. Endocrinol. 1999, 162:371 379. It has beenreported that the detrimental effects of glucocorticoids on bone noduleformation can be lessened by administration of carbenoxolone, which is anon-specific 11β-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125.Additional reports suggest that 11β-HSD1 can be responsible forproviding increased levels of active glucocorticoid in osteoclasts, andthus in augmenting bone resorption. Cooper et al., Bone 2000,27:375-381. This data suggests that inhibition of 11β-HSD1 may havebeneficial effects against osteoporosis via one or more mechanisms whichmay act in parallel.

It is known that bile acids inhibit 11β-HSD2 and that such inhibitionresults in a shift in the cortisol/cortisone equilibrium in the favor ofcortisol. Quattropani et al., J. Clin. Invest. November 2001,108:1299-305. A reduction in the hepatic activity of 11β-HSD2 istherefore predicted to reverse the cortisol/cortisone equilibrium tofavor cortisone, which could provide therapeutic benefit in diseasessuch as hypertension.

The various isozymes of the 17-beta-hydroxysteroid dehydrogenases(17β-HSDs) bind to androgen receptors or estrogen receptors and catalyzethe interconversion of various sex hormones including estradiol/estroneand testosterone/androstenedione. To date, six isozymes have beenidentifed in humans and are expressed in various human tissues includingendometrial tissue, breast tissue, colon tissue, and in the testes.17-beta-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is expressed inhuman endometrium and its activity has been reported to be linked tocervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab., 2000,85:1371-3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3(17β-HSD3) is expressed in the testes and its modulation can be usefulfor the treatment of androgen-related disorders.

Androgens and estrogens are active in their 17β-hydroxy configurations,whereas their 17-keto derivatives do not bind to androgen and estrogenreceptors and are thus inactive. The conversion between the active andinactive forms (estradiol/estrone and testosterone/androstenedione) ofsex hormones is catalyzed by members of the 17β-HSD family. 17β-HSD1catalyzes the formation of estradiol in breast tissue, which isimportant for the growth of malignant breast tumors. Labrie et al., Mol.Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggestedfor 17β-HSD4 in colon cancer. English et al., J. Clin. Endocrinol.Metab. 1999, 84:2080-2085. 17β-HSD3 is almost exclusively expressed inthe testes and converts androstenedione into testosterone. Deficiency ofthis enzyme during fetal development leads to malepseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both17β-HSD3 and various 3α-HSD isozymes are involved in complex metabolicpathways which lead to androgen shuffles between inactive and activeforms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation ofcertain HSDs can have potentially beneficial effects in the treatment ofandrogen- and estrogen-related disorders.

The 20-alpha-hydroxysteroid dehydrogenases (20α-HSDs) catalyze theinterconversion of progestins (such as between progesterone and20α-hydroxy progesterone). Other substrates for 20α-HSDs include17α-hydroxypregnenolone or 17α-hydroxyprogesterone, leading to 20α-OHsteroids. Several 20α-HSD isoforms have been identified and 20α-HSDs areexpressed in various tissues, including the placenta, ovaries, testesand adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23: 1-11.

The 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs) catalyze theinterconversion of the androgens dihydrotestosterone (DHT) and5α-androstane-3α,17β-diol and the interconversion of the androgens DHEAand androstenedione and therefore play an important role in androgenmetabolism. Ge et al., Biology of Reproduction 1999, 60:855-860.

Despite the previous research done in the field of HSD inhibition, thereremains a need for novel compounds that are potent inhibitors of thevarious families of HSDs and efficacious for the treatment ofHSD-mediated conditions such as diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression,hypertension, and others.

BRIEF SUMMARY OF THE INVENTION

The present invention satisfies this need and others by providing novelcompounds, compositions thereof and methods for modulating the activityof hydroxysteroid dehydrogenases (HSDs), such as 11β-hydroxysteroiddehydrogenases, 17β-hydroxysteroid dehydrogenases, 20α-hydroxysteroiddehydrogenases, and 3α-hydroxysteroid dehydrogenases, including allisoforms thereof, including but not limited to 11β-hydroxysteroiddehydrogenase type 1 (hereinafter “11β-HSD1”), 11β-hydroxysteroiddehydrogenase type 2 (hereinafter “11β-HSD2”), and 17β-hydroxysteroiddehydrogenase type 3 (hereinafter “17β-HSD3”). In one embodiment, thecompounds of the invention inhibit HSD activity.

The present invention also relates to methods for treating or preventingdiseases or disorders associated with the action of hydroxysteroiddehydrogenases, comprising administering to a patient in need thereof atherapeutically effective amount of a diaza heterocyclic amidederivative of formula I or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, or a mixture thereof. The inventionencompasses both selective and non-selective inhibitors ofhydroxysteroid dehydrogenases.

It should be understood that selective and non-selective inhibitors ofhydroxysteroid dehydrogenases each have benefits in the treatment orprevention of diseases associated with, for example, abnormal glucoselevels or hypothalmic function. The invention also encompasses selectiveinhibitors of HSDs. Two types of selectivity are contemplated, that withrespect to selectivity for HSDs as a class over other types of receptorsor gene targets related to glucose metabolism, or those which areselective for various HSDs or specific isoforms thereof compared toother HSDs or specific isoforms thereof.

In one embodiment, the diaza heterocyclic amide derivatives can act asselective or non-selective 11β-HSD inhibitors. The compounds may inhibitthe interconversion of inactive 11-keto steroids with their activehydroxy equivalents. The present invention provides methods by which theconversion of the inactive to the active form can be controlled, anduseful therapeutic effects which can be obtained as a result of suchcontrol. More specifically, but not exclusively, the invention isconcerned with interconversion between cortisone and cortisol in humans.

In another embodiment, the diaza heterocyclic amide derivatives of thepresent invention can be orally active.

The diaza heterocyclic amide derivatives are also useful for themodulation of numerous metabolic functions including, but not limitedto, one or more of: (i) regulation of carbohydrate metabolism, (ii)regulation of protein metabolism, (iii) regulation of lipid metabolism,(iv) regulation of normal growth and/or development, (v) influence oncognitive function, (vi) resistance to stress and mineralocorticoidactivity.

The diaza heterocyclic amide derivatives are additionally useful forinhibiting hepatic gluconeogenesis, and they also can be effective torelieve the effects of endogenous glucocorticoids in diabetes mellitus,obesity (including entripetal obesity), neuronal loss and/or thecognitive impairment of old age. Thus, in a further aspect, theinvention provides the use of an inhibitor of HSDs in methods directedto producing one or more therapeutic effects in a patient to whom thediaza heterocyclic amide derivative is administered, said therapeuticeffects selected from the group consisting of inhibition of hepaticgluconeogenesis, an increase in insulin sensitivity in adipose tissueand muscle, and the prevention of or reduction in neuronalloss/cognitive impairment due to glucocorticoid-potentiatedneurotoxicity or neural dysfunction or damage.

The invention further provides methods for treating a condition selectedfrom the group consisting of: hepatic insulin resistance, adipose tissueinsulin resistance, muscle insulin resistance, neuronal loss ordysfunction due to glucocorticoid potentiated neurotoxicity, and anycombination of the aforementioned conditions, the methods comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a diaza heterocyclic amide derivative.

The diaza heterocyclic amide derivatives of the invention are compoundshaving Formula (I):

or pharmaceutically acceptable salts, solvates, stereoisomers, orprodrugs thereof.

X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen.

R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxyand (C₁-C₄)alkylene-C(O)R⁴.

R² and R³ are independently selected from hydrogen, halogen, hydroxy,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; or R² andR³ can be combined to form a (C₃-C₈)cycloalkane ring.

R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and(C₃-C₈)heterocycloalkyl.

R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when Xis halogen, then R⁵ is not hydrogen.

R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹²,(C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and(C₁-C₈)haloalkyl.

R⁷ is selected from hydrogen and (C₁-C₈)alkyl.

R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and(C₁-C₈)alkyl; or R⁹ can be combined with R⁶ or R⁷ to form a bridgedbicyclic ring;

Y is selected from the group consisting of hydrogen, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl.

Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl,O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkyleneoptionally interrupted with one or more oxygens, wherein n, at eachoccurrence, is 0 or 1.

When Q is a bond, then Y is not hydrogen.

R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted withone or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and(C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl.

The subscript m is 1 or 2.

Any cycloalkyl portion, heterocycloalkyl portion, aryl portion orheteroaryl portion is optionally substituted with from one to fourmembers selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl,halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl,—C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂,—S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′.

Each occurrence of R′ is independently hydrogen or an unsubstitutedmember selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl or two R′ groups, whenattached to the same nitrogen atom, is combined with the nitrogen atomto which they are attached to form a heterocycle or a heteroaryl group.

Each occurrence of R″ is independently an unsubstituted member selectedfrom (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.

It should be understood that Formula I does not include the followingcompounds:

-   2-[[4-[(4-methylphenyl)sulfonyl]-1-piperazinyl]carbonyl-benzoic    acid,-   1-(4-methylbenzoyl)-4[(4-methylphenyl)sulfonyl])-piperazine,-   1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxopropyl]-4-[(4-methylphenyl)sulfonyl]-piperazine,-   N-[2-(4-fluorophenyl)ethyl]-4-[(4-methylphenyl)sulfonyl]-gamma-oxo-1-piperazinebutanamide,-   3-chloro-N-(2-[4-[(4-methylphenyl)sulfonyl]-1-piperazineyl]-2-oxoethyl]-5-nitro    benzamide,-   1-[[4-(2-methylphenyl)-5-(4-pyridinyl)-4H-1,2,4-triazol-3-ylthio]acetyl]-4-[(4-methylphenyl)sulfonyl]-piperazine,-   1-[[[3,4-3,4-dihydro-4-oxo-3-phenyl-2-quinazolinyl]thio]acetyl]-4-[(4-methylphenyl)sulfonyl]-piperazine,-   1-[(4-methylphenyl)sulfonyl]-4-[[5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)thio]acetyl]-piperazine,-   1-[[[3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]thio]acetyl]-4-[[4-methylphenyl)sulfonyl]-piperazine,-   1-[(2,4-dimethylphenyl)sulfonyl]-4-(phenylacetyl)-piperazine, and-   2-(methylthio)-2-[4-[(4-methylphenyl)sulfonyl]-1-piperazinyl]-2-oxoethyl    benzoic acid.

One embodiment of the invention provides a pharmaceutical compositioncomprising a diaza heterocyclic amide derivative of Formula (I) and apharmaceutically acceptable vehicle, carrier, excipient or diluent.

In another embodiment, the invention provides methods for treatinginsulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative derivative of Formula (I).

In another embodiment, the invention provides methods for treatingnon-insulin-dependent diabetes mellitus comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I).

In yet another embodiment, the invention provides a method for treatinginsulin resistance comprising administering to a patient in need thereofa therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In still another embodiment, the invention provides a method fortreating obesity comprising administering to a patient in need thereof atherapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In another embodiment, the invention provides a method for modulatingcortisol production comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In another embodiment, the invention provides methods for modulatinghepatic glucose production comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In another embodiment, the invention provides a method for modulatinghypothalamic function comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In one embodiment, the invention provides a method for treating ahydroxysteroid dehydrogenase-mediated condition or disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a diaza heterocyclic amide derivative of Formula (I).

In a further embodiment, the invention provides a method for modulatinga hydroxysteroid dehydrogenase, comprising administering to a patient inneed thereof a therapeutically effective amount of a diaza heterocyclicamide derivative of Formula (I).

In still another embodiment, the invention provides a method fortreating an 11β-HSD1-mediated condition or disorder comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a diaza heterocyclic amide derivative of Formula (I).

In yet another embodiment, the invention provides a method formodulating the function of 11β-HSD1 in a cell comprising administeringto a patient in need thereof a therapeutically effective amount of adiaza heterocyclic amide derivative of Formula (I).

In a further embodiment, the invention provides a method for modulating11β-HSD1, comprising administering to a patient in need thereof atherapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In one embodiment, the invention provides a method for treating an11β-HSD2-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I).

In another embodiment, the invention provides a method for modulatingthe function of 11β-HSD2 in a cell comprising administering to a patientin need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I).

In a further embodiment, the invention provides a method for modulating11β-HSD2, comprising administering to a patient in need thereof atherapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

In one embodiment, the invention provides a method for treating an17β-HSD3-mediated condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I).

In another embodiment, the invention provide a method for modulating thefunction of 17β-HSD3 in a cell comprising administering to a patient inneed thereof a therapeutically effective amount of a diaza heterocyclicamide derivative of Formula (I).

In a further embodiment, the invention provides a method for modulating17β-HSD3, comprising administering to a patient in need thereof atherapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I).

These and other embodiments of this invention will be evident uponreference to the following detailed description. To that end, certainpatent and other documents are cited herein to more specifically setforth various embodiments of this invention. Each of these documents arehereby incorporated by reference in their entireties.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the terms have the following meanings:

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆)alkyl is meant to include, but is not limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein below.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C₈)alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈)alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkylene” refers to a divalent alkyl group (e.g., an alkylgroup attached to two other moieties, typically as a linking group).Examples of a (C₁-C₇)alkylene include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, and—CH₂CH₂CH₂CH₂CH₂CH₂CH₂—, as well as branched versions thereof. Analkylene group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The term “alkenylene” refers to a divalent alkene group (e.g., an alkenegroup attached to two other moieties, typically as a linking group).Examples of a (C₂-C₇)alkenylene include —CH═CH—, —CH═CHCH₂—,—CH═CHCH₂CH₂—, —CH═CHCH₂CH₂CH₂—, —CH═CHCH₂CH₂CH₂CH₂—, and—CH═CHCH₂CH₂CH₂CH₂CH₂—, as well as branched versions and structureisomers thereof. An alkenylene group can be unsubstituted or optionallysubstituted with one or more substituents as described herein below.

The term “alkoxy” as used herein refers to an —O-alkyl group having theindicated number of carbon atoms. For example, a (C₁-C₆)alkoxy groupincludes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,—O-sec-butyl, —O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl,—O-hexyl, —O-isohexyl, and —O-neohexyl.

The term “aminoalkyl,” as used herein, refers to an alkyl group(typically one to six carbon atoms) wherein from one or more of theC₁-C₆ alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(a))₂, wherein each occurrence of R^(a) is independently —H or(C₁-C₆)alkyl. Examples of aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂—, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl and the like.

The term “aryl” as used herein refers to a 6- to 14-membered monocyclic,bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of anaryl group include phenyl and naphthyl. An aryl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclichydrocarbon ring system. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, decahydronaphthalene, octahydronaphthalene,hexahydronaphthalene, octahydroindene, hexahydroindene, tetrahydroinden,decahydrobenzocycloheptene, octahydrobenzocycloheptene,hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene,dodecahydroheptalene, decahydroheptalene, octahydroheptalene,hexahydroheptalene, and tetrahydroheptalene. A cycloalkyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “halo” as used herein refers to —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to a C₁-C₆ alkyl groupwherein from one or more of the C₁-C₆ alkyl group's hydrogen atom isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainalkyl, or combinations thereof, consisting of carbon atoms and from oneto three heteroatoms selected from the group consisting of O, N and S,and wherein the nitrogen and sulfur atoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized. The heteroatom(s)O, N and S can be placed at any position of the heteroalkyl group.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, and—CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive, such as, forexample, —CH₂—NH—OCH₃. When a prefix such as (C₂-C₈) is used to refer toa heteroalkyl group, the number of carbons (2 to 8, in this example) ismeant to include the heteroatoms as well. For example, a C₂-heteroalkylgroup is meant to include, for example, —CH₂OH (one carbon atom and oneheteroatom replacing a carbon atom) and —CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group is an oxyalkyl group. Forinstance, (C₂-C₅)oxyalkyl is meant to include, for example —CH₂—O—CH₃ (aC₃-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, and the like.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members and having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom,including monocyclic, bicyclic, and tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, andquinoxalinyl. A heteroaryl group can be unsubstituted or optionallysubstituted with one or more substituents as described herein below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

As used herein, the term “heterocycle” refers to 3- to 14-membered ringsystems which are either saturated, unsaturated, or aromatic, and whichcontains from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms canbe optionally oxidized, and the nitrogen heteroatom can be optionallyquaternized, including, including monocyclic, bicyclic, and tricyclicring systems. The bicyclic and tricyclic ring systems may encompass aheterocycle or heteroaryl fused to a benzene ring. The heterocycle canbe attached via any heteroatom or carbon atom. Heterocycles includeheteroaryls as defined above. Representative examples of heterocyclesinclude, but are not limited to, aziridinyl, oxiranyl, thiiranyl,triazolyl, tetrazolyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl,azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl,morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, dioxanyl,triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl,furanyl, furazanyl, pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl,thiazolyl, benzthiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl and quinazolinyl. A heterocycle group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “heterocycloalkyl,” by itself or in combination with otherterms, represents, unless otherwise stated, cyclic versions of“heteroalkyl.” Additionally, a heteroatom can occupy the position atwhich the heterocycle is attached to the remainder of the molecule.Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, and the like.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group havingthe indicated number of carbon atoms wherein one or more of the alkylgroup's hydrogen atoms is replaced with an —OH group. Examples ofhydroxyalkyl groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

Substituents for the groups referred to as alkyl, heteroalkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halo, —SiR′R″ R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″,—NR′″SO₂NR′R″, —NR″CO₂R′, —NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and —NO₂, in a number rangingfrom zero to three, with those groups having zero, one or twosubstituents being exemplary. R′, R″ and R′″ each independently refer tohydrogen, unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl and aryl substituted with one to three substituentsselected from -halo, unsubstituted alkyl, unsubstituted alkoxy,unsubstituted thioalkoxy and unsubstituted aryl(C₁-C₄)alkyl. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, analkyl or heteroalkyl group will have from zero to three substituents,with those groups having two or fewer substituents being exemplary ofthe present invention. An alkyl or heteroalkyl radical can beunsubstituted or monosubstituted. In some embodiments, an alkyl orheteroalkyl radical will be unsubstituted. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups such as trihaloalkyl (e.g., —CF₃ and—CH₂CF₃).

Exemplary substituents for the alkyl and heteroalkyl radicals includebut are not limited to —OR′, ═O, —NR′R″, —SR′, -halo, —SiR′R″ R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR″CO₂R′, —NR′″SO₂NR′R″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —CN and—NO₂, where R′, R″ and R′″ are as defined above. Typical substituentscan be selected from: —OR′, ═O, —NR′R″, -halo, —OC(O)R′, —CO₂R′,—C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′″SO₂NR′R″, —SO₂R′,—SO₂NR′R″, —NR″SO₂R′ —CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: -halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —C(O)NR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′″C(O)NR′R″, —NR′″SO₂NR′R″, —NHC(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R′, —N₃, —CH(Ph)₂,perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, in a number ranging from zeroto the total number of open valences on the aromatic ring system; andwhere R′, R″ and R′″ are independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl, unsubstituted heteroaryl, unsubstitutedaryl(C₁-C₄)alkyl and unsubstituted aryloxy(C₁-C₄)alkyl. Typically, anaryl or heteroaryl group will have from zero to three substituents, withthose groups having two or fewer substituents being exemplary in thepresent invention. In one embodiment of the invention, an aryl orheteroaryl group will be unsubstituted or monosubstituted. In anotherembodiment, an aryl or heteroaryl group will be unsubstituted.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringin an aryl or heteroaryl group may optionally be replaced with asubstituent of the formula -T-C(O)—(CH₂)_(q)—U—, wherein T and U areindependently —NH—, —O—, —CH₂— or a single bond, and q is an integer offrom 0 to 2. Alternatively, two of the substituents on adjacent atoms ofthe aryl or heteroaryl ring may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— is selected fromhydrogen or unsubstituted (C₁-C₆)alkyl.

It is to be understood that the substituent —CO₂H, as used herein, canbe optionally replaced with bioisosteric replacements such as:

and the like. See, e.g., The Practice of Medicinal Chemistry; Wermuth,C. G., Ed.; Academic Press: New York, 1996; p. 203.

The diaza heterocyclic amide derivative of formula I can also exist invarious isomeric forms, including configurational, geometric andconformational isomers, as well as existing in various tautomeric forms,particularly those that differ in the point of attachment of a hydrogenatom. As used herein, the term “isomer” is intended to encompass allisomeric forms of a diaza heterocyclic amide derivative, includingtautomeric forms of the compound.

Certain diaza heterocyclic amide derivatives may have asymmetric centersand therefore exist in different enantiomeric and diastereomeric forms.A diaza heterocyclic amide derivative can be in the form of an opticalisomer or a diastereomer. Accordingly, the invention encompasses diazaheterocyclic amide derivatives and their uses as described herein in theform of their optical isomers, diasteriomers and mixtures thereof,including racemic mixtures. Optical isomers of the diaza heterocyclicamide derivatives can be obtained by known techniques such as asymmetricsynthesis, chiral chromatography, simulated moving bed technology or viachemical separation of stereoisomers through the employment of opticallyactive resolving agents.

As used herein and unless otherwise indicated, the term “stereoisomer”means one stereoisomer of a compound that is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecompound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. A typical stereomerically pure compoundcomprises greater than about 80% by weight of one stereoisomer of thecompound and less than about 20% by weight of other stereoisomers of thecompound, for example greater than about 90% by weight of onestereoisomer of the compound and less than about 10% by weight of theother stereoisomers of the compound, or greater than about 95% by weightof one stereoisomer of the compound and less than about 5% by weight ofthe other stereoisomers of the compound, or greater than about 97% byweight of one stereoisomer of the compound and less than about 3% byweight of the other stereoisomers of the compound.

It should be noted that if there is a discrepancy between a depictedstructure and a name given to that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold, wedged,or dashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

A diaza heterocyclic amide derivative can be in the form of apharmaceutically acceptable salt. Depending on the structure of thederivative, the phrase “pharmaceutically acceptable salt,” as usedherein, refers to a pharmaceutically acceptable organic or inorganicacid or base salt of a diaza heterocyclic amide derivative.Representative pharmaceutically acceptable salts include, e.g., alkalimetal salts, alkali earth salts, ammonium salts, water-soluble andwater-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.Furthermore, a pharmaceutically acceptable salt can have more than onecharged atom in its structure. In this instance the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounterions.

As used herein, the term “isolated and purified form” means that whenisolated (e.g., from other components of a synthetic organic chemicalreaction mixture), the isolate contains at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or at least 98% of a diaza heterocyclic amidederivative by weight of the isolate. In one embodiment, the isolatecontains at least 95% of a diaza heterocyclic amide derivative by weightof the isolate.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound, particularly adiaza heterocyclic amide derivative. Examples of prodrugs include, butare not limited to, derivatives and metabolites of a diaza heterocyclicamide derivative that include biohydrolyzable groups such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues (e.g., monophosphate, diphosphate ortriphosphate). In some embodiments, prodrugs of compounds with carboxylfunctional groups are the lower alkyl esters of the carboxylic acid. Thecarboxylate esters are conveniently formed by esterifying any of thecarboxylic acid moieties present on the molecule. Prodrugs can typicallybe prepared using well-known methods, such as those described byBurger's Medicinal Chemistry and Drug Discovery 6^(th) ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication or amelioration of a disease or symptoms associated witha disease. In certain embodiments, such terms refer to minimizing thespread or worsening of the disease resulting from the administration ofone or more prophylactic or therapeutic agents to a patient with such adisease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the onset, recurrence or spread of the disease in apatient resulting from the administration of a prophylactic ortherapeutic agent.

The term “effective amount” as used herein refers to an amount of adiaza heterocyclic amide derivative or other active ingredientsufficient to provide a therapeutic or prophylactic benefit in thetreatment or prevention of a disease or to delay or minimize symptomsassociated with a disease. Further, a therapeutically effective amountwith respect to a diaza heterocyclic amide derivative means that amountof therapeutic agent alone, or in combination with other therapies, thatprovides a therapeutic benefit in the treatment or prevention of adisease. Used in connection with a diaza heterocyclic amide derivative,the term can encompass an amount that improves overall therapy, reducesor avoids symptoms or causes of disease, or enhances the therapeuticefficacy of or synergies with another therapeutic agent.

As used herein, “syndrome X” refers to a collection of abnormalitiesincluding hyperinsulinemia, obesity, elevated levels of triglycerides,uric acid, fibrinogen, small dense LDL particles and plasminogenactivator inhibitor 1 (PAI-1), and decreased levels of HDL cholesterol.Syndrome X is further meant to include metabolic syndrome.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, 11β-HSD1. “Modulation”, as used herein in its various forms, isintended to encompass inhibition, antagonism, partial antagonism,activation, agonism and/or partial agonism of the activity associatedwith 11β-HSD1. 11β-HSD1 inhibitors are compounds that, e.g., bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. 11β-HSD1 activators are compounds that, e.g., bind to,stimulate, increase, open, activate, facilitate, enhance activation,sensitize or up regulate signal transduction. The ability of a compoundto modulate 11β-HSD1 can be demonstrated in an enzymatic assay or acell-based assay. For example, the inhibition of 11β-HSD1 may decreasecortisol levels in a patient and/or increase cortisone levels in apatient by blocking the conversion of cortisone to cortisol.Alternatively, the inhibition of 11β-HSD2 can increase cortisol levelsin a patient and/or decrease cortisone levels in a patient by blockingthe conversion of cortisol to cortisone.

A “patient” includes an animal (e.g., cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), in oneembodiment a mammal such as a non-primate or a primate (e.g., monkey andhuman), and in another embodiment a human. In a one embodiment, apatient is a human. In other embodiments, the patient is a human infant,child, adolescent or adult.

The term “HSD” as used herein, refers to hydroxysteroid dehydrogenaseenzymes in general, including, but not limited to,11-beta-hydroxysteroid dehydrogenases (11β-HSDs), 17-beta-hydroxysteroiddehydrogenases (17β-HSDs), 20-alpha-hydroxysteroid dehydrogenases(20α-HSDs), 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs), and allisoforms thereof.

The term “11β-HSD1” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 1 enzyme, variant, or isoform thereof. 11β-HSD1variants include proteins substantially homologous to native 11β-HSD1,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD1derivatives, homologs and fragments). The amino acid sequence of a11β-HSD1 variant can be at least about 80% identical to a native11β-HSD1, or at least about 90% identical, or at least about 95%identical.

The term “11β-HSD2” as used herein, refers to the 11-beta-hydroxysteroiddehydrogenase type 2 enzyme, variant, or isoform thereof. 11β-HSD2variants include proteins substantially homologous to native 11β-HSD2,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD2derivatives, homologs and fragments). The amino acid sequence of a11β-HSD2 variant can be at least about 80% identical to a native11β-HSD2, or at least about 90% identical, or at least about 95%identical. (see Bart et al., J. Med. Chem., 2002, 45:3813-3815).

The term “17β-HSD3” as used herein, refers to the 17-beta-hydroxysteroiddehydrogenase type 3 enzyme, variant, or isoform thereof. 17β-HSD3variants include proteins substantially homologous to native 17β-HSD3,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 17β-HSD3derivatives, homologs and fragments). The amino acid sequence of a17β-HSD3 variant can be at least about 80% identical to a native17β-HSD3, or at least about 90% identical, or at least about 95%identical.

As used herein, the term “HSD-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of a hydroxysteroid dehydrogenase enzyme (HSD).Favorable responses to HSD modulation include alleviation or abrogationof the disease and/or its attendant symptoms, inhibition of the disease,i.e., arrest or reduction of the development of the disease, or itsclinical symptoms, and regression of the disease or its clinicalsymptoms. An HSD-responsive condition or disease can be completely orpartially responsive to HSD modulation. An HSD-responsive condition ordisorder can be associated with inappropriate, e.g., less than orgreater than normal, HSD activity and at least partially responsive toor affected by HSD modulation (e.g., an HSD inhibitor results in someimprovement in patient well-being in at least some patients).Inappropriate HSD functional activity might arise as the result of HSDexpression in cells which normally do not express HSD, decreased HSDexpression or increased HSD expression. An HSD-responsive condition ordisorder may include condition or disorder mediated by any HSD orisoform thereof.

As used herein, the term “11β-HSD1-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD1 activity. Favorable responses to11β-HSD1 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD1-responsive condition or disease can be completely or partiallyresponsive to 11β-HSD1 modulation. An 11β-HSD1-responsive condition ordisorder can be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD1 activity and at least partially responsiveto or affected by 11β-HSD1 modulation (e.g., a 11β-HSD1 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 11β-HSD1 functional activity might arise as theresult of 11β-HSD1 expression in cells which normally do not express11β-HSD1, decreased 11β-HSD1 expression or increased 11β-HSD1expression. A 11β-HSD1-responsive condition or disorder may include a11β-HSD1-mediated condition or disorder.

As used herein, the term “11β-HSD2-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD2 activity. Favorable responses to11β-HSD2 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An11β-HSD2-responsive condition or disease can be completely or partiallyresponsive to 11β-HSD2 modulation. An 11β-HSD2-responsive condition ordisorder can be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD2 activity and at least partially responsiveto or affected by 11β-HSD2 modulation (e.g., a 11β-HSD2 inhibitorresults in some improvement in patient well-being in at least somepatients).

As used herein, the term “17β-HSD3-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 17β-HSD3 activity. Favorable responses to17β-HSD3 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease, i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms, and regression of the disease or its clinical symptoms. An17β-HSD3-responsive condition or disease can be completely or partiallyresponsive to 17β-HSD3 modulation. An 17β-HSD3-responsive condition ordisorder can be associated with inappropriate, e.g., less than orgreater than normal, 17β-HSD3 activity and at least partially responsiveto or affected by 17β-HSD3 modulation (e.g., a 17β-HSD3 inhibitorresults in some improvement in patient well-being in at least somepatients). Inappropriate 17β-HSD3 functional activity might arise as theresult of 17β-HSD3 expression in cells which normally do not express17β-HSD3, decreased 17β-HSD3 expression or increased 17β-HSD3expression. A 17β-HSD3-responsive condition or disorder may include a17β-HSD3-mediated condition or disorder.

As used herein, the term “HSD-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, activity of ahydroxysteroid dehydrogenase (HSD). An HSD-mediated condition ordisorder can be completely or partially characterized by inappropriateHSD activity. However, an HSD-mediated condition or disorder is one inwhich modulation of an HSD results in some effect on the underlyingcondition or disease (e.g., an HSD inhibitor results in some improvementin patient well-being in at least some patients).

As used herein, the term “11β-HSD1-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD1activity. A 11β-HSD1-mediated condition or disorder can be completely orpartially characterized by inappropriate 11β-HSD1 activity. However, a11β-HSD1-mediated condition or disorder is one in which modulation of11β-HSD1 results in some effect on the underlying condition or disease(e.g., a 11β-HSD1 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “11β-HSD2-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD2activity. A 11β-HSD2-mediated condition or disorder can be completely orpartially characterized by inappropriate 11β-HSD2 activity. However, a11β-HSD2-mediated condition or disorder is one in which modulation of11β-HSD2 results in some effect on the underlying condition or disease(e.g., a 11β-HSD2 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “17β-HSD3-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 17β-HSD3activity. A 17β-HSD3-mediated condition or disorder can be completely orpartially characterized by inappropriate 17β-HSD3 activity. However, a17β-HSD3-mediated condition or disorder is one in which modulation of17β-HSD3 results in some effect on the underlying condition or disease(e.g., a 17β-HSD3 inhibitor results in some improvement in patientwell-being in at least some patients).

The following abbreviations are used herein and have the indicateddefinitions: DMEM is Dulbecco's Modified Eagle Medium; Et₃N istriethylamine; EtOAc is ethyl acetate; MeOH is methanol; MS is massspectrometry; NMR is nuclear magnetic resonance; PBS isphosphate-buffered saline; SPA is scintillation proximity assay; THF istetrahydrofuran; and TMS is trimethylsilyl.

Compounds of the Invention

The present invention provides compounds of Formula (I) as well as theirpharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs,or mixtures thereof, collectively referred to as “the diaza heterocyclicamide derivatives:”

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, wherein all the variables are defined as above.

In one embodiment, the subscript m is 1. In another embodiment, thesubscript m is 2.

In some embodiments, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen and X is—C(R¹)(R²)(R³).

In some embodiments, X is —C(R¹)(R²)(R³) and R¹, R² and R³ areindependently selected from (C₁-C₃)alkyl, —OH, and (C₁-C₃)haloalkyl; andR⁶ is selected from hydrogen, (C₁-C₈)alkyl, aryl, heteroaryl, and(C₁-C₈)haloalkyl.

In some other embodiments, R¹ is methyl, and wherein R² istrifluoromethyl and R³ is —OH.

In yet another embodiment, R¹ is methyl, R² is methyl, and R³ is methyl.In still another embodiment R¹, R², and R³ are all hydrogen.

In some embodiments R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen.

In other embodiments, X and R⁵ are halogen.

In some other embodiments, m is 1, R⁶ is methyl, and R⁷, R⁸, R⁹, and R¹⁰are hydrogen.

In some embodiments, R⁶ and R⁸ are (C₁-C₃)alkyl, in particular methyl,and R⁷, R⁹, and R¹⁰ are hydrogen.

In still other embodiments, R⁹ and R¹⁰ are (C₁-C₃)alkyl, in particularmethyl, and R⁶, R⁷, and R⁸ are hydrogen.

In another embodiment, X is:

In still another embodiment, X is:

The diaza heterocyclic amide derivatives can have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. Thisinvention relates to the use of all optical isomers and stereoisomers ofthe diaza heterocyclic amide derivatives, and mixtures thereof, and toall pharmaceutical compositions and methods of treatment that may employor contain them.

It should be noted that racemates, racemic mixtures, and stereoisomers,particularly diastereomeric mixtures or diastereomerically purecompounds and enantiomers or enantiomerically pure compounds of theabove are all contemplated.

Specific examples of compounds of Formula I are provided below:

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

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90

91

92

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95

96

97

98

99

100

The present invention also provides compositions comprising a diazaheterocyclic amide derivative of Formula (I) and a pharmaceuticallyacceptable vehicle, carrier, diluent or excipient.

The invention further provides diaza heterocyclic amide derivatives ofFormula (I) that are in isolated and purified form.

The invention provides methods for treating diabetes comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a diaza heterocyclic amide derivative of Formula (I) or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, or a mixture thereof.

The invention also provides methods for treating obesity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a diaza heterocyclic amide derivative of Formula (I) or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, or a mixture thereof.

The invention further provides methods for treating an HSD-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I) or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, or a mixture thereof.

The invention further provides methods for treating an 11β-HSD1-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I) or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, or a mixture thereof.

The invention further provides methods for treating an 11β-HSD2-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I) or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, or a mixture thereof.

The invention further provides methods for treating an 17β-HSD3-mediatedcondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I) or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, or a mixture thereof.

The invention further provides methods for treating an HSD-responsivecondition or disorder comprising administering to a patient in needthereof a therapeutically effective amount of a diaza heterocyclic amidederivative of Formula (I) or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, or a mixture thereof.

The invention further provides methods for treating an11β-HSD1-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I) or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixturethereof.

The invention further provides methods for treating an11β-HSD2-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I) or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixturethereof.

The invention further provides methods for treating an17β-HSD3-responsive condition or disorder comprising administering to apatient in need thereof a therapeutically effective amount of a diazaheterocyclic amide derivative of Formula (I) or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixturethereof.

Preparation of the Diaza Heterocyclic Amides of Formula I

Those skilled in the art will recognize that there are a variety ofmethods available to synthesize molecules represented in the claims.

General Synthesis Methods

In general, useful methods for synthesizing compounds represented in theclaims consist generally of four parts, which may be done in any order:Formation of a sulfonamide bond, installation and/or modification of theX group, installation and/or modification of functional groups appendedto the central diaza ring and the —R¹¹ group, and formation of theaza-amide bond. Retrosynthetic disconnection of the compounds of theinvention into fragments a-d useful for construction of the compounds,is shown below:

Several methods for the preparation of claimed compounds are preferred(eq. 1-3). Equation one demonstrates one method of forming thesulfonamide linkage. In the case of eq. 1 Z is chosen from anappropriate group such as Cl and F, or additionally from any groupcapable of activating a sulfonyl group for displacement by an amine(i.e. OSu, imidazole, etc.).

The coupling referred to in eq. 1 may be assisted by the use of organicor inorganic bases, activating agents, and also by catalysts, inparticular by those catalysts known in the art which assist in theformation of sulfonamide bonds such as DMAP etc. Exemplary couplingpartners include sulfonyl chloride and amine, sulfonyl fluoride andamine, SO₂OSu and amine and so forth. Those skilled in the art willrecognize there are other possible combinations which will also resultin the desired product.

Formation of the amide bond may be accomplished via a variety ofmethods, one of which is exemplified in eq. 2. Coupling of the diazaring with an appropriately substituted carbonyl moiety can beaccomplished via typical amide bond forming conditions. In some casesthe coupling may be accelerated by the inclusion of organic or inorganicbases such as triethylamine, Hunig's base, potassium carbonate, and soforth. Example coupling partners include diazaheterocycle and acidfluoride, acid chloride, or additionally from any group capable ofactivating a carboxylic acid for displacement by an amine (i.e. OSu,imidazole, etc.), to name a few. The coupling may be assisted by theinclusion of catalysts, in particular by those catalysts known in theart which assist in the formation of amide bonds such as DMAP, HOBT,etc. Elaboration to compounds of the invention is then accomplished asin equation one.

Alternatively, the diazaheterocycle-amide bond may be made afterformation of the sulfonamide bond, as exemplified in equation three andutilizing the same variety of conditions described above. Those skilledin the art will understand that this may or may not be advantageousdepending on the substituent pattern in the desired compound. Furthermodification as in the earlier equations then yields compounds of theinvention.

A variety of the methods described above have been used to preparecompounds of the invention, some of which are exemplified in theexamples.

Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising adiaza heterocyclic amide derivative, or a pharmaceutically acceptablestereoisomer, prodrug, salt, solvate, hydrate, or clathrate thereof, arealso encompassed by the invention. Individual dosage forms of theinvention can be suitable for oral, mucosal (including sublingual,buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous,intramuscular, bolus injection, intraarterial, or intravenous),transdermal, or topical administration.

Examples of dosage forms include, but are not limited to: tablets;caplets; capsules, such as soft elastic gelatin capsules; cachets;troches; lozenges; dispersions; suppositories; ointments; cataplasms(poultices); pastes; powders; dressings; creams; plasters; solutions;patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosageforms suitable for oral or mucosal administration to a patient,including suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,effervescent compositions, and elixirs; liquid dosage forms suitable forparenteral administration to a patient; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disease may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

This invention further encompasses anhydrous (e.g., <1% water)pharmaceutical compositions and dosage forms comprising activeingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. See, e.g., Jens T. Carstensen, DrugStability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y.,1995, pp. 379-80. In effect, water and heat accelerate the decompositionof some compounds. Thus, the effect of water on a formulation can be ofgreat significance since moisture and/or humidity are commonlyencountered during manufacture, handling, packaging, storage, shipment,and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The diaza heterocyclic amide derivatives of formula I can beadministered to a mammal (human, horse, mouse, rat, rabbit, dog, cat,bovine, pig, monkey etc.) as an 11β-HSD1 modulator, a prophylactic ortherapeutic drug of diabetes, a prophylactic or therapeutic drug ofdiabetic complication (retinopathy, nephropathy, neuropathy, cardiacinfarction and cerebral infarction based on arteriosclerosis etc.), aprophylactic or therapeutic drug of hyperlipemia, a prophylactic ortherapeutic drug of obesity, neurodegenerative disease and the like, ora prophylactic or therapeutic drug of diseases mediated by 11β-HSD1.

The diaza heterocyclic amide derivatives can be administered to a mammalconcurrently with an additional therapeutic agent for the treatment of adisease, such as diabetes or obesity, with the aim of the prophylaxis ortreatment of a disease. As such, the diaza heterocyclic amidederivatives of the present invention can be administered in combinationwith other therapeutic agents for the treatment or prevention ofnumerous diseases, including, but not limited to, diabetes and obesity.

Depending on the disease to be treated and the patient's condition, thecompounds of the invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and can be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the case of a combined administration, the diaza heterocyclic amidederivatives can be administered simultaneously with other anothertherapeutic agent that is useful for the treatment or prevention ofdiabetes, obesity or other disease or can be administered at a timeprior to or subsequent to another therapeutic agent. In the case ofcombined administration, a pharmaceutical composition containing thediaza heterocyclic amide derivative and an additional therapeutic agentcan be administered. Alternatively, a pharmaceutical compositioncontaining the diaza heterocyclic amide derivative and a pharmaceuticalcomposition containing an additional therapeutic agent can beadministered separately. The administration routes of respectivepharmaceutical compositions can be the same or different.

In the case of a combined administration, the diaza heterocyclic amidederivatives can be administered at a dose of 50 mg to 800 mg peradministration, which is given up to several times a day. For example,dosing of once per day or less than once per day is contemplated (e.g.,once weekly). In addition, the compound can be administered at a smallerdose. The combined pharmaceutical agent can be administered at a dosegenerally employed for the prophylaxis or treatment of diabetes orobesity or at a smaller dose than that.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise adiaza heterocyclic amide derivative, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymoprh or prodrug thereof. In thetreatment or prevention of diabetes, obesity, glaucoma, osteoporosis,cognitive disorders, immune disorders, depression or other conditions ordisorders associated with the modulation of an hydroxysteroiddehydrogenase, an appropriate dosage level will generally be from about0.001 to about 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. An exemplary dosage level canbe from about 0.01 to about 25 mg/kg per day or about 0.05 to about 10mg/kg per day. In other embodiments, a suitable dosage level can be fromabout 0.01 to about 25 mg/kg per day, about 0.05 to about 10 mg/kg perday, or about 0.1 to about 5 mg/kg per day. Within this range the dosagecan be from about 0.005 to about 0.05, about 0.05 to about 0.5 or about0.5 to about 5.0 mg/kg per day lie within the range of from about 0.1 mgto about 2000 mg per day, given as a single once-a-day dose in themorning but typically as divided doses throughout the day taken withfood. In one embodiment, the daily dose is administered twice daily inequally divided doses. A daily dose range can be from about 5 mg toabout 500 mg per day or between about 10 mg and about 300 mg per day. Inmanaging the patient, the therapy can be initiated at a lower dose, suchas from about 1 mg to about 25 mg, and increased if necessary up to fromabout 200 mg to about 2000 mg per day as either a single dose or divideddoses, depending on the patient's global response.

For multidrug therapy, the weight ratio of the compound of the inventionto the second active ingredient can be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a compound of the invention iscombined with an NSAID, the weight ratio of the compound of theinvention to the NSAID will generally range from about 1000:1 to about1:1000, such as from about 200:1 to about 1:200. Combinations of acompound of the invention and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and can be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

For oral administration, the compositions can be provided in the form oftablets containing about 1 to about 1000 milligrams of the activeingredient. In other embodiments, the compositions are provided inprovided in the form of tablets containing about 1.0, about 5.0, about10.0, about 15.0. about 20.0, about 25.0, about 50.0, about 75.0, about100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0,about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, orabout 1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds canbe administered on a regimen of 1 to 4 times per day, such as once ortwice per day.

Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

Controlled-release pharmaceutical products can improve drug therapy overthat achieved by their non-controlled counterparts. Ideally, the use ofan optimally designed controlled-release preparation in medicaltreatment is characterized by a minimum of drug substance being employedto cure or control the condition in a minimum amount of time. Advantagesof controlled-release formulations include extended activity of thedrug, reduced dosage frequency, and increased patient compliance. Inaddition, controlled-release formulations can be used to affect the timeof onset of action or other characteristics, such as blood levels of thedrug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms can be sterile or capableof being sterilized prior to administration to a patient. Examples ofparenteral dosage forms include, but are not limited to, solutions readyfor injection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions. For example, lyophilized sterile compositionssuitable for reconstitution into particulate-free dosage forms suitablefor administration to humans.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

In some embodiments, parenteral dosage forms used for the methods ofpreventing, treating or managing disease in a cancer patient.

Transdermal and Topical Dosage Forms

Transdermal and topical dosage forms of the invention include, but arenot limited to, creams, lotions, ointments, gels, solutions, emulsions,suspensions, or other forms known to one of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, EastonPa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal and topical dosage formsencompassed by this invention are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants also can be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

Depending on the specific tissue to be treated, additional componentscan be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Mucosal Dosage Forms and Lung Delivery

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

A compound of the invention can also be administered directly to thelung by inhalation (see e.g., Tong et al., International Publication No.WO 97/39745; Clark et al, International Publication No. WO 99/47196,which are herein incorporated by reference). For administration byinhalation, a diaza heterocyclic amide derivative can be convenientlydelivered to the lung by a number of different devices. For example, aMetered Dose Inhaler (“MDI”) which utilizes canisters that contain asuitable low boiling propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas can be used to deliver a diaza heterocyclic amidederivative directly to the lung. MDI devices are available from a numberof suppliers such as 3M Corporation, Aventis, Boehringer Ingleheim,Forest Laboratories, Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a diaza heterocyclic amide derivative to the lung (See, e.g.,Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999,40, 397, which is herein incorporated by reference). DPI devicestypically use a mechanism such as a burst of gas to create a cloud ofdry powder inside a container, which can then be inhaled by the patient.DPI devices are also well known in the art and can be purchased from anumber of vendors which include, for example, Fisons, Glaxo-Wellcome,Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. Apopular variation is the multiple dose DPI (“MDDPI”) system, whichallows for the delivery of more than one therapeutic dose. MDDPI devicesare available from companies such as AstraZeneca, GlaxoWellcome, IVAX,Schering Plough, SkyePharma and Vectura. For example, capsules andcartridges of gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch for these systems.

Another type of device that can be used to deliver a diaza heterocyclicamide derivative to the lung is a liquid spray device supplied, forexample, by Aradigm Corporation. Liquid spray systems use extremelysmall nozzle holes to aerosolize liquid drug formulations that can thenbe directly inhaled into the lung.

In one embodiment, a nebulizer device is used to deliver a diazaheterocyclic amide derivative to the lung. Nebulizers create aerosolsfrom liquid drug formulations by using, for example, ultrasonic energyto form fine particles that can be readily inhaled (See e.g., Verschoyleet al., British J Cancer, 1999, 80, Suppl 2, 96, which is hereinincorporated by reference). Examples of nebulizers include devicessupplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer etal., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No.5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974, which areherein incorporated by reference), Aventis and Batelle PulmonaryTherapeutics. Inhaled compounds, delivered by nebulizer devices, arecurrently under investigation as treatments for aerodigestive cancer(Engelke et al., Poster 342 at American Association of Cancer Research,San Francisco, Calif., Apr. 1-5, 2000) and lung cancer (Dahl et al.,Poster 524 at American Association of Cancer Research, San Francisco,Calif., Apr. 1-5, 2000).

In another embodiment, an electrohydrodynamic (“EHD”) aerosol device isused to deliver a diaza heterocyclic amide derivative to the lung. EHDaerosol devices use electrical energy to aerosolize liquid drugsolutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, InternationalPublication No. WO 94/12285; Coffee, International Publication No. WO94/14543; Coffee, International Publication No. WO 95/26234, Coffee,International Publication No. WO 95/26235, Coffee, InternationalPublication No. WO 95/32807, which are herein incorporated byreference). The electrochemical properties of the compound of theinvention formulation can be important parameters to optimize whendelivering this drug to the lung with an EHD aerosol device and suchoptimization is routinely performed by one of skill in the art. EHDaerosol devices may more efficiently delivery drugs to the lung thanexisting pulmonary delivery technologies. Other methods ofintra-pulmonary delivery of a diaza heterocyclic amide derivative willbe known to the skilled artisan and are within the scope of theinvention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a diazaheterocyclic amide derivative with a pharmaceutically acceptablecarrier. In some embodiments, the pharmaceutically acceptable carrier isa liquid such as alcohol, water, polyethylene glycol or aperfluorocarbon. Optionally, another material can be added to alter theaerosol properties of the solution or suspension of a diaza heterocyclicamide derivative. This material can be a liquid such as an alcohol,glycol, polyglycol or a fatty acid. Other methods of formulating liquiddrug solutions or suspension suitable for use in aerosol devices areknown to those of skill in the art (See, e.g., Biesalski, U.S. Pat. Nos.5,112,598; Biesalski, 5,556,611, which are herein incorporated byreference). A compound of the invention can also be formulated in rectalor vaginal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

In addition to the formulations described previously, a diazaheterocyclic amide derivative can also be formulated as a depotpreparation. Such long acting formulations can be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds can beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

Other Delivery Systems

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver a diaza heterocyclic amide derivative.Certain organic solvents such as dimethylsulfoxide can also be employed,although usually at the cost of greater toxicity. A compound of theinvention can also be delivered in a controlled release system. In oneembodiment, a pump can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987,14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N.Engl. J. Med, 1989, 321, 574). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol. Sci.Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science 1985,228, 190; During et al., Ann. Neurol., 1989, 25,351; Howard et al.,1989, J. Neurosurg. 71, 105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target ofthe compounds of the invention, e.g., the lung, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115 (1984)).Other controlled-release system can be used (see e.g., Langer, Science,1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site or method which a given pharmaceuticalcomposition or dosage form will be administered. With that fact in mind,typical excipients include, but are not limited to, water, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof, which arenon-toxic and pharmaceutically acceptable. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Therapeutic Uses of the Diaza Heterocyclic Amide Derivatives

In one aspect, the invention provides methods of treating or preventinga condition or disorder associated with the modulation of hydroxysteroiddehydrogenases by administering to a patient having such a condition ordisorder a therapeutically effective amount of a compound or compositionof the invention. In one group of embodiments, conditions and disorders,including chronic diseases of humans or other species, can be treatedwith modulators, stimulators, or inhibitors of hydroxysteroiddehydrogenases, such as 11β-HSD1.

Treatment or Prevention of Diabetes

Diabetes and diabetic conditions can be treated or prevented byadministration of a therapeutically effective amount of a diazaheterocyclic amide derivative.

Types of diabetes that can be treated or prevented by administering atherapeutically effective amount of a diaza heterocyclic amidederivative include type I diabetes mellitus (juvenile onset diabetes,insulin dependent-diabetes mellitus or IDDM), type II diabetes mellitus(non-insulin-dependent diabetes mellitus or NIDDM), insulinopathies,diabetes associated with pancreatic disorders, diabetes associated withother disorders (such as Cushing's Syndrome, acromegaly,pheochromocytoma, glucagonoma, primary aldosteronism, andsomatostatinoma), type A and type B insulin resistance syndromes,lipatrophic diabetes, and diabetes induced by β-cell toxins.

In some embodiments, the type of diabetes being treated is type IIdiabetes.

Treatment or Prevention of Obesity

Obesity can be treated or prevented by administration of atherapeutically effective amount of a diaza heterocyclic amidederivative.

Obesity may have genetic, environmental (e.g., expending less energythan is consumed) and regulatory determinants. Obesity includesexogenous, hyperinsulinar, hyperplasmic, hypothyroid, hypothalamic,symptomatic, infantile, upper body, alimentary, hypogonadal, simple andcentral obesity, hypophyseal adiposity and hyperphagia. Metabolicdisorders, such as hyperlidemia and diabetes, and cardiovasculardisorders, such as hypertension and coronary artery disease, arecommonly associated with obesity.

Complications due to obesity may also be treated or prevented byadministering a therapeutically effective amount of a diaza heterocyclicamide derivative. Such complications include, but are not limited to,sleep apnea, Pickwickian syndrome, orthopedic disturbances ofweight-bearing and non-weight-bearing joints, and skin disordersresulting from increased sweat or skin secretions.

Treatment or Prevention of Other Conditions

Other conditions that can be treated or prevented by administering atherapeutically effective amount of a diaza heterocyclic amidederivative include, but are not limited to any condition which isresponsive to the modulation, such as inhibition, of hydroxysteroiddehydrogenases or specific isoforms thereof, and thereby benefit fromadministration of such a modulator. Representative conditions in thisregard include, but are not limited to, metabolic disorders and relatedcardiovascular risk factors such as syndrome X, polycystic ovariandisease, eating disorders (e.g., anorexia and bulimia),craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia and Cushing's syndrome; diseasesassociated therewith such as hypertension, atherosclerosis, vascularrestenosis, retinopathy and nephropathy; neurologic disorders such asneurodegenerative disease, neuropathy and muscle wasting; cognitivedisorders, such as age-related learning disorders, dementia,neurodegeneration, as well as for improvement of cognitive function insubjects ranging from the severely impaired (e.g., Parkinsons's orAlzheimer's associated dementia) to mildly impaired (e.g.,age-associated memory impairment, drug-induced cognitive impairment) tounimpaired subjects (e.g., cognitive enhancers for the generalpopulation) (see, Sandeep, et al., PNAS, electronically available atwww.pnas.org/cgi/doi/10.1073/pnas.0306996101); androgen and/orestrogen-related disorders such as prostate cancer, colon cancer, breastcancer, benign prostatic hyperplasia, ovarian cancer, uterine cancer,and male pseudohermaphrodism; endometriosis, dementia, depression,psoriasis, glaucoma, osteoporosis, viral infections, inflammatorydisorders, and immune disorders.

Additional Therapeutic Agents

In one embodiment, the present methods for treating or preventingfurther comprise the administration of a therapeutically effectiveamount of another therapeutic agent useful for treating or preventingthe diseases or disorders disclosed herein. In this embodiment, the timein which the therapeutic effect of the other therapeutic agent isexerted overlaps with the time in which the therapeutic effect of thediaza heterocyclic amide derivative is exerted.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the conditions or disorders for which compounds of theinvention are useful, including diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression andthose pathologies noted above.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with adiaza heterocyclic amide derivative. In one embodiment, a pharmaceuticalcomposition contains such other drugs in addition to the compound of theinvention when a diaza heterocyclic amide derivative is usedcontemporaneously with one or more other drugs. Accordingly, thepharmaceutical compositions of the invention include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a diaza heterocyclic amide derivative.

In one embodiment, for the treatment or prevention of diabetes, a diazaheterocyclic amide derivative can be administered with anothertherapeutic agent, including, but not limited to, anti-diabetic agentssuch as insulin, inhaled insulin (Exubera®), insulin mimetics, insulinsecretogues, sulfonylureas (e.g., glyburide, meglinatide, glimepiride,gliclazide, glipizide, gliquidone, chloropropresponsivemide,tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride,glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine,glypinamide, phenbutamide, tolcylamide and tolazamide), biguanides(e.g., metformin (Glucophage®)), α-glucosidase inhibitors (e.g.,acarbose, voglibose and miglitol), thiazolidinone compounds (e.g.,rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone,pioglitazone (Actos®) and englitazone), prandial glucose regulators(e.g., repaglinide and nateglinide) and glucagon receptor antagonists.

In another embodiment, for the treatment or prevention of obesity, adiaza heterocyclic amide derivative can be administered with anothertherapeutic agent, including, but not limited to, β3 adrenergic receptoragonists, leptin or derivatives thereof, neuropeptide Y (e.g., NPY5)antagonists, and mazindol.

Examples of other therapeutic agents that can be combined with a diazaheterocyclic amide derivative, either administered separately or in thesame pharmaceutical compositions, include, but are not limited to: (i)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin (Zocor®), pravastatin, fluvastatin, atorvastatin(Lipitor®) and other statins), bile acid sequestrants (e.g.,cholestyramine and colestipol), vitamin B₃ (also known as nicotinicacid, or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin),fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., ezitimibe (Zetia®), beta-sitosterol andacylCoA-cholesterol acyltransferase (ACAT) inhibitors such asmelinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitorsand squalene synthetase inhibitors; (ii) antithrombotic agents, such asthrombolytic agents (e.g., streptokinase, alteplase, anistreplase andreteplase), heparin, hirudin and warfarin derivatives, β-blockers (e.g.,atenolol), β adrenergic agonists (e.g., isoproterenol), angiotensin IIantagonists, ACE inhibitors and vasodilators (e.g., sodiumnitroprusside, nicardipine hydrochloride, nitroglycerin andenaloprilat); (iii) PPAR agonists, e.g., PPARγ and PPAR_(δ) agonists;(iv) DP antagonists; (v) lubricants or emollients such as petrolatum andlanolin, keratolytic agents, vitamin D₃ derivatives (e.g., calcipotrieneand calcipotriol (Dovonex®)), PUVA, anthralin (Drithrocreme®),etretinate (Tegison®) and isotretinoin; (vi) glaucoma therapies such ascholinergic agonists (e.g., pilocarpine and carbachol), cholinesteraseinhibitors (e.g., physostigmine, neostigmine, demacarium, echothiophateiodide and isofluorophate), carbonic anhydrase inhibitors (e.g.,acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide anddorzolamide), non-selective adrenergic agonists (e.g., epinephrine anddipivefrin), α₂-selecteive adrenergic agonists (e.g., apraclonidine andbrimonidine), β-blockers (e.g., timolol, betazolol, levobunolol,carteolol and metipranolol), prostaglandin analogs (e.g., latanoprost)and osmotic diuretics (e.g., glycerin, mannitol and isosorbide);corticosteroids, such as beclomethasone, methylprednisolone,betamethasone, prednisone, prenisolone, dexamethasone, fluticasone andhydrocortisone, and corticosteroid analogs such as budesonide; (vii)immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®,Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus,Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate,e.g., mycophenolate mofetil (CellCept®); (viii) non-steroidalantiinflammatory agents (NSAIDs) such as propionic acid derivatives(e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g.,indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac,sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acidderivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid,niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives(e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam,sudoxicam and tenoxican), salicylates (e.g., acetylsalicylic acid andsulfasalazine) and the pyrazolones (e.g., apazone, bezpiperylon,feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (ix)cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) androfecoxib (Vioxx®); (xi) inhibitors of phosphodiesterase type IV(PDE-IV); (xii) opioid analgesics such as codeine, fentanyl,hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone,oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine,nalbuphine and pentazocine; (xiii) a hepatoprotective agent; and (xiv)other compounds such as 5-aminosalicylic acid and prodrugs thereof.

The weight ratio of the compound of the invention to the second activeingredient can be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a diaza heterocyclic amide derivative is combined with anNSAID, the weight ratio of the compound of the invention to the NSAIDwill generally range from about 1000:1 to about 1:1000, such as about200:1 to about 1:200. Combinations of a diaza heterocyclic amidederivative and other active ingredients will generally also be withinthe aforementioned range, but in each case, an effective dose of eachactive ingredient should be used.

Kits

The invention encompasses kits that can simplify the administration ofthe diaza heterocyclic amide derivatives or composition of the inventionto a patient.

A typical kit of the invention comprises a unit dosage of a diazaheterocyclic amide derivative. In one embodiment, the unit dosage formis in a container, which can be sterile, containing a therapeuticallyeffective amount of a diaza heterocyclic amide derivative and apharmaceutically acceptable vehicle. In another embodiment, the unitdosage form is in a container containing a therapeutically effectiveamount of a diaza heterocyclic amide derivative as a lyophilate orpharmaceutically acceptable salt. In this instance, the kit can furthercomprise another container that contains a solution useful for thereconstitution of the lyophilate or dissolution of the salt. The kit canalso comprise a label or printed instructions for use of the diazaheterocyclic amide derivatives.

The kits of the instant invention may also comprise a second therapeuticagent that can be administered sequentially, separately, orconcomitantly. Non-limiting examples of such second therapeutic agentsare described hereinabove.

In a further embodiment, the kit comprises a unit dosage form of acomposition of the invention.

Kits of the invention can further comprise one or more devices that areuseful for administering the unit dosage forms of the diaza heterocyclicamide derivatives or a composition of the invention. Examples of suchdevices include, but are not limited to, a syringe, a drip bag, a patchor an enema, which optionally contain the unit dosage forms.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims. Tothis end, it should be noted that one or more hydrogen atoms or methylgroups can be omitted from the drawn structures consistent with acceptedshorthand notation of such organic compounds, and that one skilled inthe art of organic chemistry would readily appreciate their presence.

EXAMPLES

The diaza heterocyclic amide derivatives represented by the formulas ofthe present invention and the methods of making thereof are explained indetail in the following examples, which are not to be construed aslimiting the invention.

Example 1 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(phenyl)methanone

a) 1-(4-tert-Butylphenylsulfonyl)piperazine: To a 250 mL flaskcontaining 4.3 g piperazine (50.0 mmol, 2.0 equiv) and 60 mL CH₂Cl₂ wascarefully added 6.0 g 4-tert-butylbenzenesulfonyl chloride (25.0 mmol,1.0 equiv) over a period of 15 min. The reaction was allowed to stir for2 h at which time it was diluted with sat. NaHCO₃. The solution was thenextracted (3×CH₂Cl₂), dried (Na₂SO₄), and concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 0-5% MeOH/CH₂Cl₂with 1% NH₄OH) gave the product as a white solid.

b) (4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(phenyl)methanone: Aflask was charged with 48 mg (0.17 mmol, 1.0 equiv)1-(4-tert-butylphenylsulfonyl)piperazine and 1 mL CH₂Cl₂. The resultingsolution was cooled in an ice bath to 0° C. followed by the addition of0.47 mL triethylamine (0.34 mmol, 2.0 equiv) and 21.1 mg benzoylchloride (0.15 mmol, 0.9 equiv). After stirring for 15 min the solutionwas diluted with sat. NaHCO₃ and extracted (2×CH₂Cl₂). The CH₂Cl₂solution was then dried (Na₂SO₄) and concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 0-2% MeOH/CH₂Cl₂)gave the product as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (d,J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.43-7.27 (m, 5H), 3.84-3.55 (br,4H), 2.97 (br, 4H), 1.37 (s, 9H).

Using the methods described above in Example 1, the following compoundswere prepared substituting the appropriate carboxylic chloride forbenzoyl chloride in step (b).

Example 2 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(3-chlorophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(3-chlorophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.67 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.41-7.19 (m, 4H), 3.83-3.53 (br, 4H), 2.98 (br, 4H), 1.37 (s, 9H).

Example 3 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(2-chlorophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(2-chlorophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.36-7.29 (m, 3H), 7.20 (d, 1H), 3.95 (m, 1H), 3.83 (m, 1H),3.35-3.30 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 1.37 (s, 9H).

Example 4 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(3,4-difluorophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(3,4-difluorophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.67 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.23-7.09 (m, 3H), 3.61 (br, 4H), 3.03 (br, 4H), 1.37 (s, 9H).

Example 5 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(2,6-difluorophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(2,6-difluorophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.33 (m, 1H), 6.92 (m, 2H), 3.90 (m, 2H), 3.41 (m, 2H), 3.20 (m,2H), 3.01 (m, 2H), 1.35 (s, 9H).

Example 6 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(3-nitrophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(3-nitrophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 8.29 (d, J=8.1 Hz, 1H), 8.20 (s, 1H),7.69-7.56 (m, 6H), 3.87-3.53 (br, 4H), 3.01 (br, 4H), 1.37 (s, 9H).

Example 7 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(naphthalen-1-yl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(naphthalen-1-yl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.87 (d, J=8.1 Hz, 1H), 7.67-7.32 (m, 10H),4.02 (m, 2H), 3.30-3.17 (m, 4H), 2.86 (m, 2H), 1.39 (s, 9H).

Example 8 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(2,3-dichlorophenyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(2,3-dichlorophenyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.11 (m, 1H), 3.97(m, 1H), 3.77 (m, 1H), 3.33-2.96 (m, 6H), 1.35 (s, 9H).

Example 9 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(thiophen-2-yl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(thiophen-2-yl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 7.45 (d, J=5.0 Hz, 1H), 7.26 (m, 1H), 7.03 (m, 1H), 3.86 (m, 4H),3.06 (m, 4H), 1.35 (s, 9H).

Example 10 Synthesis of1-(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)-2-cyclopentylethanone

1-(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)-2-cyclopentylethanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz,2H), 3.68 (m, 2H), 3.54 (m, 2H), 2.96 (m, 4H), 2.26 (d, J=7.1 Hz, 1H),2.14 (m, 1H), 1.75 (m, 2H), 1.50 (m, 4H), 1.35 (s, 9H), 1.04 (m, 2H).

Example 11 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(1-methylcyclohexyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(1-methylcyclohexyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.66 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.5 Hz,2H), 3.73 (m, 4H), 2.99 (m, 4H), 1.90 (m, 2H), 1.44-1.32 (m, 17H), 1.14(s, 3H).

Example 12 Synthesis of(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)(cyclobutyl)methanone

(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)(cyclobutyl)methanone: ¹HNMR (CDCl₃, 400 MHz) δ 7.68 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H),3.67 (m, 2H), 3.42 (m, 2H), 3.15 (m, 1H), 2.95 (m, 4H), 2.24 (m, 2H),2.08 (m, 2H), 1.89 (m, 2H), 1.33 (s, 3H).

Example 13 Synthesis of1-(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)-2-phenylethanone

1-(4-(4-tert-Butylphenylsulfonyl)piperazin-1-yl)-2-phenylethanone: ¹HNMR (CDCl₃, 400 MHz) δ 7.59 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H),7.23 (m, 3H), 7.14 (m, 2H), 3.72 (m, 2H), 3.68 (s, 2H), 3.50 (m, 2H),2.95 (m, 2H), 2.73 (m, 2H), 1.38 (s, 3H).

Example 14-A Synthesis of1,1,1-trifluoro-2-(4-((R)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol

a) (R)-tert-Butyl4-(4-acetylphenylsulfonyl)-3-methylpiperazine-1-carboxylate: To a 250 mLflask containing 8.98 g (R)-tert-butyl 3-methylpiperazine-1-carboxylate(48.2 mmol, 1.0 equiv), 9.75 g triethylamine (96.4 mmol, 2.0 equiv) and100 mL CH₂Cl₂ was added 10.5 g 4-acetylbenzenesulfonyl chloride (48.2mmol, 1.0 equiv). The reaction was allowed to stir for 12 h at whichtime it was diluted with sat. NaHCO₃. The solution was then extracted(3×CH₂Cl₂), dried (Na₂SO₄), and concentrated under reduced pressure.Purification by flash chromatography (SiO₂, 0-1% MeOH/CH₂Cl₂) gave theproduct as a white solid.

b)(3R)-tert-Butyl-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsulfonyl)piperazine-1-carboxylate:A 100 mL flask containing the product obtained above (4.9 g, 13.3 mmol,1.0 equiv) was charged with 50 mL TMS-CF₃ (0.5M in THF) at 0° C. Thesolution was allowed to stir for 0.5 h followed by addition of 25 μLtetrabutylammnium fluoride (1.0M in THF) at 0° C. After stirring for 1h, the solution was diluted with sat. NaHCO₃, extracted (2×10%MeOH/CH₂Cl₂). The organics were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash chromatography (SiO₂, 2%MeOH/CH₂Cl₂) gave the product as an off-white solid.

c)1,1,1-Trifluoro-2-(4-((R)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol:To a 250 mL flask containing the product obtained above (4.5 g, 9.9mmol) and 20 mL DCM was added 2 mL TFA. The reaction was allowed to stirfor 12 h at which time it was diluted with sat. NaHCO₃. The solution wasthen extracted (3×CH₂Cl₂), dried (Na₂SO₄), and concentrated underreduced pressure. Purification by flash chromatography (SiO₂, 0-5%MeOH/CH₂Cl₂ with 1% NH₄OH) gave the product as a white solid.

Example 14 Synthesis ofcyclopropyl((R-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsulfonyl)piperazin-1-yl)methanone

Using the methods described above in example one, substituting1,1,1-trifluoro-2-(4-((R)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-olfor 1-(4-tert-butylphenylsulfonyl)piperazine and cyclopropanecarbonylchloride for benzoyl chloride in step (b), the following was prepared:cyclopropyl((R)-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsulfonyl)piperazin-1-yl)methanone:¹H NMR (CDCl₃, 500 MHz) δ 7.86 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.5 Hz,2H), 4.0-2.7 (br, 7H), 1.88 (br, 1H), 1.83 (s, 3H), 1.09-1.02 (m, 2H),0.79 (m, 2H).

Example 15 Synthesis of1-(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)-2-(pyridin-2-yl)ethanone

A 25 mL flask was charged with 60 mg 2-(pyridin-4-yl)acetic acid (0.35mmol, 1.0 equiv), 150 mg 1-(4-tert-butylphenylsulfonyl)piperazine (0.53mmol, 1.5 equiv), 378 mgO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 0.88 mmol, 2.1 equiv), and 119 mg 1-hydroxybenzotriazole hydrate(HOBT, 0.88 mmol, 2.1 equiv). The flask was then charged with 5 mL DMF,stirring was initiated (magnetic stirrer) and 0.97 mL N-methylmorpholine(NMM, 0.88 mmol, 2.1 equiv) was added in one portion to the suspension.After 12 h, the suspension was diluted with 20 mL sat. NaHCO₃ andextracted (2×CH₂Cl₂). The CH₂Cl₂ solution was then dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 0-5% MeOH/CH₂Cl₂) gave the product as a whitesolid: ¹H NMR (CDCl₃, 400 MHz) δ 8.50 (d, J=5.2 Hz, 2H), 7.70 (d, J=8.5Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.09 (d, J=5.3 Hz, 2H), 3.73 (m, 2H),3.65 (s, 2H), 3.53 (m, 2H), 2.99 (m, 2H), 2.89 (m, 2H), 1.36 (s, 3H).

Example 16 Synthesis of((R-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsulfonyl)piperazin-1-yl)(1-phenylcyclopropyl)methanone

Using the methods described above in example 15, substituting1,1,1-trifluoro-2-(4-((R)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-olfor 1-(4-tert-butylphenylsulfonyl)piperazine and1-phenylcyclopropanecarboxylic acid for 2-(pyridin-4-yl)acetic acid instep (a), the following was prepared:((R)-3-methyl-4-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsulfonyl)piperazin-1-yl)(1-phenylcyclopropyl)methanone:¹H NMR (CDCl₃, 400 MHz) δ 7.76 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.5 Hz,2H), 7.30-7.00 (m, 5H), 4.0-2.7 (br, 7H), 1.85 (s, 3H), 1.23 (s, 3H)1.0-0.7 (m, 4H).

Example 17 Synthesis of(4-(4-tert-butylphenylsulfonyl)-3-(hydroxymethyl)piperazin-1-yl)(cyclopropyl)methanone

a) (4-Benzyl-1-(4-tert-butylphenylsulfonyl)piperazin-2-yl)methanol: 233mg (4-Benzylpiperazin-2-yl)methanol (1.13 mmol, 1.0 equiv, prepared asin Naylor et. al., J. Med. Chem. 1993, 36, 2075-2083) in 20 mL CH₂Cl₂was combined in a flask with 237 mg 4-tert-butylbenzene-1-sulfonylchloride (1.01 mmol, 0.9 equiv) and 149 mg triethylamine (1.47 mmol, 1.3equiv). The solution was allowed to stir for 12 h followed by dilutionwith 20 mL CH₂Cl₂. and sat. NaHCO₃. The aqueous solution was extracted(2×10% MeOH/CH₂Cl₂) and the organics were dried (MgSO₄) and concentratedunder reduced pressure. Purification by flash chromatography (SiO₂,0˜2.5% MeOH/CH₂Cl₂) gave the product as a colorless oil.

b) (1-(4-tert-Butylphenylsulfonyl)piperazin-2-yl)methanol: A 1 L flaskwas charged with 500 mg 10% Pd/C and 400 mL EtOH under N₂. The productobtained above (6.23 g, 15.5 mmol, 1.0 equiv) in 10 mL EtOH was added,followed by 150 mL cyclohexene. The flask was equipped with a refluxcondenser, and then placed into a preheated 84° C. bath. After stirringfor 12 h, the solution was hot filtered through a plug of celite and thecelite plug was washed 3×EtOH. The organics were dried (MgSO₄) andconcentrated under reduced pressure. Purification was accomplished byflash chromatography (SiO₂, 1% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂ with 1%NH₄OH).

c)(4-(4-tert-Butylphenylsulfonyl)-3-(hydroxymethyl)piperazin-1-yl)(cyclopropyl)methanone:(1-(4-tert-butylphenylsulfonyl)piperazin-2-yl)methanol (288 mg, 0.922mmol, 1.0 equiv) was dissolved in 10 mL CH₂CL₂ followed by the additionof 0.167 mL triethylamine (1.20 mmol, 1.3 equiv) and 0.081 mLcyclopropylcarbonyl chloride (0.876 mmol, 0.95 equiv). After stirringfor 30 minutes, the solution was diluted with saturated NaHCO₃, followedby stirring for an additional 10 minutes. The solution was then pouredinto a 3M Empore octadecyl (C18) SD cartridge, and the organics thatpassed through were concentrated under reduced pressure to give theproduct as a white solid.

Example 18(4-(4-tert-Butylphenylsulfonyl)-3-(methoxymethyl)piperazin-1-yl)(cyclopropyl)methanone

(4-(4-tert-Butylphenylsulfonyl)-3-(methoxymethyl)piperazin-1-yl)(cyclopropyl)methanone:(1-(4-tert-Butylphenylsulfonyl)piperazin-2-yl)methanol (97 mg, 0.255mmol, 1.0 equiv, prepared as described in example 17) was dissolved in 5mL THF under N₂ followed by the addition of 0.1 mL DMF, 0.079 mL methyliodide (0.765 mmol, 3.0 equiv) and 18 mg sodium hydride (1.28 mmol, 5.0equiv). The solution was allowed to stir for one hour, at which time thesolution was diluted with a saturated NaHCO₃ solution. The resultingsolution was extracted (3×CH₂Cl₂), dried (Na₂SO₄), and concentratedunder reduced pressure. Purification by flash chromatography (SiO₂,0.5-2% MeOH/CH₂Cl₂) gave the product as a white solid. ¹H NMR (DMSO, 400MHz) δ 7.79 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 4.21-3.90 (m,3H), 3.65 (m, 1H), 3.45-2.65 (m, 8H), 1.82 (m, 1H), 1.30 (s, 9H), 0.683(broad s, 4H).

Example 19 Synthesis of1-(4-(4-tert-butylphenylsulfonyl)-1,4-diazepan-1-yl)-2-phenylethanone

Using the methods described in example 1, substituting homopiperazinefor piperazine in step a and phenylacetyl chloride for benzoyl chloridethe following example was made:1-(4-(4-tert-butylphenylsulfonyl)-1,4-diazepan-1-yl)-2-phenylethanone:¹H NMR (CDCl₃, 400 MHz)

7.67 (m, 2H), 7.51 (m, 2H), 7.27-7.18 (m, 5H), 3.75-3.58 (m, 6H), 3.33(dd, J=3.5, 5.2 Hz, 1H), 3.16 (dd, J=6.5, 12.5 Hz, 2H), 3.01 (m, 1H),1.97 (m, 1H), 1.83 (m, 1H), 1.35 (s, 9H).

Biological Examples Procedures Useful for the Biological Evaluation ofthe Diaza Heterocyclic Amide Derivatives

In addition to the extensive literature disclosing the role of HSDs invarious diseases and disorders, described herein are assays useful fortesting the diaza heterocyclic amide derivatives of the presentinvention.

Assays

In vitro 11β-HSD1 (hydroxysteroid dehydrogenase 1) Activity InhibitoryAction

The 11β-HSD1 inhibitory activity was examined by quantitativedetermination by an SPA (scintillation proximity assay) system of thesuppressive action on the conversion from cortisone to cortisol usinghuman 11β-HSD1 (hereinafter recombinant 11β-HSD1) expressed using abaculo-virus system as an enzyme source. For the reaction, a reagent wasadded to a 96 well plate (96 well Opti-Plates™-96 (Packard)) to thefollowing final concentration and a volume of 100 μl was reacted at roomtemperature for 90 min. The reaction solution used was 0.1 μg/mlrecombinant 11β-HSD1, 500 μM NADPH, 16 nM ³H cortisone (AmershamBiosciences, 1.78 Tbq/mol) dissolved in 0.1% BSA (Sigma)-containing PBSand the test drug was 2 μl of a compound solution (dissolved in DMSO).After 90 min, the reaction was stopped by adding PBS (40 μl, containing0.1% BSA (Sigma)) containing 0.08 μg of anti-cortisol mouse monoclonalantibody (East Coast Biologics), 365 μg SPA PVT mouse antibody-bindingbeads (Amersham Biosciences) and 175 μM carbenoxolone (Sigma) to thereaction solution. After the completion of the reaction, the plate wasincubated overnight at room temperature and the radioactivity wasmeasured by Topcount (Packard). For control, the value (0% inhibition)of the well containing 2 μl of DMSO instead of the test drug was used,and for positive control, the value (100% inhibition) of the wellcontaining carbenoxolone instead of the test drug at the finalconcentration of 50 μM was used. The inhibition (%) of the test drug wascalculated by ((value of control−value of test drug)/(value ofcontrol−value of positive control))×100(%). The IC₅₀ value was analyzedusing a computer-based curve fitting software.

This following example provides assays that are useful in evaluating andselecting a compound that modulates 11β-HSD1.

Biochemical 11β-HSD1 Assay by SPA

Recombinant human, mouse and rat 11β-HSD1 were expressed in baculovirusexpression system, isolated by affinity purification and used as theenzyme sources for cortisone to cortisol conversion in vitro.³H-Cortisone (Amersham Bioscience, 1.78 Tbq/mol. 49 Ci/mmol) was used asthe substrate, and a monoclonal anti-cortisol antibody and thescintillation proximity assay (SPA) system were used to detect theproduct of the 11β-HSD1-catalyzed reaction, ³H-cortisol. Reactions tookplace at room temperature for 90 min. in 96-well Opti-Plates™-96(Packard) in 100 μL volume with 2 μL test compounds or control in DMSO,0.1 μg/mL 11β-HSD1 protein, 500 μM NADPH and 16 nM radioactivecortisone, in PBS buffer supplemented with 0.1% BSA (Sigma). Reactionwas stopped with the addition of 40 μL buffer containing 0.08 μganti-cortisol monoclonal antibody (East Coast Biologics), 365 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 175 μM carbenoxolone(Sigma).

Plates were incubated at room temperature overnight before being read ona Topcount (Packard). The point of 50% inhibition of 11β-HSD1 enzymeactivity (IC₅₀) was determined by computer-based curve fitting.

Cell-Based 11β-HSD1 Assay by SPA

This cell-based assay measures the conversion of ³H-cortisone to³H-cortisol in a HEK-293 cell line stably overexpressing humanrecombinant 11β-HSD1. HEK-293 cells were grown in DMEM/F12 supplementedwith 10% fetal bovine serum, and plated onto poly-D-lysine-coated96-well assay plates (Costar 3903), 100,000 cells per well in 50 μLassay media (phenol free DMEM/F12 (Invitrogen)+0.2% BSA+1%antibiotic-antimycotic solutions). The solution was incubated at 37° C.for 24 h, and the reaction was initiated by the addition of 25 μL ofassay media containing compounds of desired concentration and 25 μL ofassay media containing 40 nM of ³H-cortisone to each well. The reactionmixture was incubated at 37° C. for 90 min. and the reaction terminatedby the addition of 25 μL of assay media containing 0.2 μg ofanti-cortisol monoclonal antibody (East Coast Biologics), 500 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 500 μM carbenoxolone(Sigma).

Plates were incubated at room temperature for at least 2 h before beingread on Topcount (Packard). The point of 50% inhibition of 11β-HSD1enzyme activity (IC₅₀) was determined by computer-based curve fitting.

Scintillation Proximity Assay

[1,2(n)-³H]-cortisone was purchased from Amersham Pharmacia Biotech.Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained fromImmunotech and Scintillation proximity assay (SPA) beads coated withmonoclonal antimouse antibodies were from Amersham Pharmacia Biotech.NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate(G-6-P) was supplied by Sigma. The human 11β-hydroxysteroiddehydrogenase type-1 enzyme (11-β-HSD₁) was expressed in Pichiapastoris. 18-β-glycyrrhetinic acid (GA) was obtained from Sigma. Theserial dilutions of the compounds were performed on a Tecan Genesis RSP150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in50 mM Tris-HCl, pH 7.2 containing 1 mM EDTA.

The multiplication of plates was done on a WallacQuadra. The amount ofthe product [³H]-cortisol, bound to the beads was determined in aPackard, Top Count microplate liquid scintillation counter.

The 11-β-HSD₁ enzyme assay was carried out in 96 well microtiter plates(Packard, Optiplate) in a total well volume of 220 μL and contained 30mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiatedCortisone/NADPH (175 nM/181 μM), G-6-P (1 mM) and inhibitors in serialdilutions (9 to 0.15 μM). Reactions were initiated by the addition ofhuman 11β-HSD₁, either as Pichia pastoris cell homogenate or microsomesprepared from Pichia pastoris (the final amount of enzyme used wasvaried between 0.057 to 0.11 mg/mL). Following mixing, the plates wereshaken for 30 to 45 minutes at room temperature. The reactions wereterminated with 10 μL 1 mM GA stop solution. Monoclonal mouse antibodywas then added (10 μL of 4 μM) followed by 100 μL of SPA beads(suspended according to the manufacturers instructions). Appropriatecontrols were set up by omitting the 11-β-HSD₁ to obtain thenon-specific binding (NSB) value.

The plates were covered with plastic film and incubated on a shaker for30 minutes, at room temperature, before counting. The amount of[³H]-cortisol, bound to the beads was determined in a microplate liquidscintillation counter. The calculation of the K_(i) values for theinhibitors was performed by use of Activity Base. The K_(i) value iscalculated from IC₅₀ and the K_(m) value is calculated using the ChengPrushoff equation (with reversible inhibition that follows theMichaelis-Menten equation): K_(i)=IC₅₀(1+[S]/K_(m)) [Cheng, Y. C.;Prushoff, W.H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The IC₅₀ ismeasured experimentally in an assay wherein the decrease of the turnoverof cortisone to cortisol is dependent on the inhibition potential ofeach substance.

Cloning, Expression and Purification of 11β-HSD1

The expression and purification of the murine enzyme is described by J.Zhang, et al. Biochemistry, 44, 2005, pp 6948-57. The expression andpurification of the human enzyme is similar to that of the murinesequence.

Enzyme Assay:

The IC50 and Ki of the compounds are determined by the following method:

1. Prepare an Assay Buffer, (pH 7.2, 50 mM Tris-HCL, 1 mM EDTA) fresheach week.

2. Prepare the following solutions:

-   -   NADPH (Sigma, 200 μM)    -   ³H-Cortisone (Amersham Biosciences, 45 Ci/mmol, 200 nM)    -   Enzyme Prep (20 nM for human, 10 nM for mouse)    -   Cortisol Antibody (East Coast Biologicals, (1:50 dilution)    -   Anti-mouse SPA beads (Amersham Biosciences, 15 mg/ml)    -   18β-Glycyrrhetinic acid (“GA”) (Aldrich, 1 μM)    -   Compound Stock Solution (10 mM in DMSO), serially diluted in        assay buffer. Each compound is tested at six different        concentrations usually (10 μM to 0.1 nM). All of the solutions        and dilutions are made in the Assay Buffer.

3. Assay is run using white/white, 96-well assay plates (Corning) in atotal volume of 100 μL.

4. Into each well of a 96-well plate is added Assay Buffer (30 μL),compound (10 μL) NADPH (10 μL), and ³H-cortisone (10 μL).

5. Initiate reaction by adding 40 μL of HSD-1 enzyme prep to the wells.

6. The plate is covered with tape and incubated on an orbital shaker for1 h at RT.

7. After 1 h, the tape is removed and anti-cortisol antibody (10 μL), GAsolution (10 μL), and SPA bead preparation (100 μL) is added.

8. The plate is incubated (30 min) on an orbital shaker at RT.

9. The counts are read on a TopCount NXT reader.

10. A dose-response curve is first plotted using the Graphpad Prismsoftware, to generate the IC50 values.

With this IC50 value and the known Km value for the substrate and HSD1enzyme, an estimated Ki can be calculated with the Chen and Prusoffequation {Ki=IC50/[1+(substrate/Km)]}.

The compounds prepared in the foregoing examples exhibited β-HSD1 enzymeactivity (IC₅₀) in the assays ranging from <1 nM to 1000 nM.

1.-8. (canceled)
 9. A method for treating a condition or disorder, the method comprising administering to a patient suffering from said condition or disorder a therapeutically effective amount of a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halogen, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl; R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl: wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group; wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; wherein the condition or disorder is selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, muscle wasting, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immune disorder.
 10. The method according to claim 9, wherein the condition or disorder is diabetes or obesity.
 11. A method of treating a condition or disorder responsive to the modulation of a hydroxysteroid dehydrogenase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halogen, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl; R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl; wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group, wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof.
 12. The method according to claim 11, wherein said hydroxysteroid dehydrogenase is selected from the group consisting of 11β-HSD1, 11β-HSD2 and 17β-HSD3.
 13. A method of modulating the function of a hydroxysteroid dehydrogenase in a cell, comprising contacting said cell with a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halogen, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl: R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl; wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₁-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group; wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)Cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.
 14. The method according to claim 13, wherein the compound inhibits hydroxysteroid dehydrogenase.
 15. A method of modulating the function of 11β-HSD1 in a cell, comprising contacting said cell with a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halo en, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl; R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl; wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group; wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.
 16. A method of modulating the function of 11β-HSD2 in a cell, comprising contacting said cell with a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl: optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halogen, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl; R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl; wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group; wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.
 17. A method of modulating the function of 17β-HSD3 in a cell, comprising contacting said cell with a compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a mixture thereof, wherein: X is selected from —C(R¹)(R²)(R³), (C₂-C₈)alkynyl, and halogen; R¹ is selected from hydrogen, hydroxy, halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₈)heterocycloalkyl, cyano, nitro, (C₁-C₈)alkoxy and (C₁-C₄)alkylene-C(O)R⁴; R² and R³ are independently selected from hydrogen, halogen, hydroxy, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl and (C₃-C₈)cycloalkyl; optionally, R² and R³ are combined to form a (C₃-C₈)cycloalkane ring; R⁴ is selected from hydroxyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, and (C₃-C₈)heterocycloalkyl; R⁵ is selected from hydrogen, (C₁-C₈)alkyl, and halogen, wherein when X is halogen, then R⁵ is not hydrogen; R⁶ is selected from hydrogen, (C₁-C₈)alkyl, (C₁-C₄)alkylene-OR¹², (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl, aryl, heteroaryl, and (C₁-C₈)haloalkyl; R⁷ is selected from hydrogen and (C₁-C₈)alkyl; R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, and (C₁-C₈)alkyl; optionally, R⁹ is combined with R⁶ or R⁷ to form a bridged bicyclic ring; Q is selected from the group consisting of a bond, (C₃-C₈)cycloalkyl, O_(n)—(C₁-C₈)alkyl-O_(n), S_(n)—(C₁-C₈)alkyl-S_(n), and (C₁-C₈)alkylene optionally interrupted with one or more oxygens; wherein n, at each occurrence, is 0 or 1; Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)cycloalkyl; wherein when Q is a bond, then Y is not hydrogen; R¹² is selected from hydrogen, (C₁-C₈)alkyl optionally interrupted with one or more oxygens, —C(O)—(C₁-C₈)alkyl, —SO₂—(C₁-C₈)alkyl and (C₃-C₈)heterocycloalkyl(C₁-C₄)alkyl; the subscript m is 1 or 2; wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —N(R′)₂ and —NR′C(O)R′; wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)heterocycloalkyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl; optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group; wherein each occurrence of R″ is independently an unsubstituted member selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)hydroxyalkyl, (C₃-C₈)cycloalkyl(C₃-C₈)heterocycloalkyl, heteroaryl, aryl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, heterocyclyl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and aryl(C₁-C₆)alkyl.
 18. A method according to any one of claims 9, 11, 13, 15, 16, and 17 wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof. 